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Science China. Life Sciences Apr 2015The protein prenylation is one of the essential post-translational protein modifications, which extensively exists in the eukaryocyte. It includes protein farnesylation... (Review)
Review
The protein prenylation is one of the essential post-translational protein modifications, which extensively exists in the eukaryocyte. It includes protein farnesylation and geranylgeranylation, using farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) as the substrate, respectively. The prenylation occurs by covalent addition of these two types of isoprenoids to cysteine residues at or near the carboxyl terminus of the proteins that possess CaaX motif, such as Ras small GTPase family. The attachment of hydrophobic prenyl groups can anchor the proteins to intracellular membranes and trigger downstream cell signaling pathway. Geranylgeranyl biphosphate synthase (GGPPS) catalyzes the synthesis of 20-carbon GGPP from 15-carbon FPP. The abnormal expression of this enzyme will affect the relative content of FPP and GGPP, and thus disrupts the balance between protein farnesylation and geranylgeranylation, which participates into various aspects of cellular physiology and pathology. In this paper, we mainly review the property of this important protein post-translational modification and research progress in its regulation of cigarette smoke induced pulmonary disease, adipocyte insulin sensitivity, the inflammation response of Sertoli cells, the hepatic lipogenesis and the cardiac hypertrophy.
Topics: Cardiomegaly; Diterpenes; Humans; Protein Prenylation
PubMed: 25862656
DOI: 10.1007/s11427-015-4836-1 -
Biochemical and Biophysical Research... Mar 2003
Review
Topics: Alkyl and Aryl Transferases; Animals; Dimethylallyltranstransferase; Humans; Kinetics; Magnesium; Metals; Models, Chemical; Protein Prenylation; Protein Processing, Post-Translational; Substrate Specificity
PubMed: 12646157
DOI: 10.1016/s0006-291x(03)00323-1 -
Annual Review of Genetics 1992
Review
Topics: Amino Acid Sequence; Animals; GTP-Binding Proteins; Genes, ras; Lamins; Molecular Sequence Data; Nuclear Proteins; Pheromones; Protein Prenylation; Protein Processing, Post-Translational
PubMed: 1482112
DOI: 10.1146/annurev.ge.26.120192.001233 -
Journal of Lipid Research Dec 1992
Review
Topics: Amino Acid Sequence; Animals; Binding Sites; Dimethylallyltranstransferase; Humans; Protein Prenylation; Proteins
PubMed: 1479283
DOI: No ID Found -
Molecular Microbiology Jan 1994Modification of proteins at C-terminal cysteine residue(s) by the isoprenoids farnesyl (C15) and geranylgeranyl (C20) is essential for the biological function of a... (Review)
Review
Modification of proteins at C-terminal cysteine residue(s) by the isoprenoids farnesyl (C15) and geranylgeranyl (C20) is essential for the biological function of a number of eukaryotic proteins including fungal mating factors and the small, GTP-binding proteins of the Ras superfamily. Three distinct enzymes, conserved between yeast and mammals, have been identified that prenylate proteins: farnesyl protein transferase, geranylgeranyl protein transferase type I and geranylgeranyl protein transferase type II. Each prenyl protein transferase has its own protein substrate specificity. Much has been learned about the biology, genetics and biochemistry of protein prenylation and prenyl protein transferases through studies of eukaryotic microorganisms, particularly Saccharomyces cerevisiae. The functional importance of protein prenylation was first demonstrated with fungal mating factors. The initial genetic analysis of prenyl protein transferases was in S. cerevisiae with the isolation and subsequent characterization of mutations in the RAM1, RAM2, CDC43 and BET2 genes, each of which encodes a prenyl protein transferase subunit. We review here these and other studies on protein prenylation in eukaryotic microbes and how they relate to and have contributed to our knowledge about protein prenylation in all eukaryotic cells.
Topics: Amino Acid Sequence; Animals; Dimethylallyltranstransferase; Genes, Fungal; Mammals; Molecular Sequence Data; Protein Prenylation; Saccharomyces cerevisiae; Substrate Specificity
PubMed: 8170384
DOI: 10.1111/j.1365-2958.1994.tb00302.x -
Cellular Signalling Sep 1996Heterotrimeric guanine nucleotide-binding regulatory proteins (G-proteins) are vital components of numerous signal transduction pathways, including sensory and hormonal... (Review)
Review
Heterotrimeric guanine nucleotide-binding regulatory proteins (G-proteins) are vital components of numerous signal transduction pathways, including sensory and hormonal response systems. G-proteins transduce signals from heptahelical transmembrane receptors to downstream effectors. The localization of a G-protein to the plasma membrane, as well as its interaction with the appropriate receptor and effector, are essential for its function. In addition, the association of a G-protein's subunits to form its trimer is required for interaction with its receptor. The G-protein gamma subunits (G gamma) are subject to a set of carboxyl-terminal processing events that include prenylation of a cysteine, proteolysis, and methylation. Recent advances which elucidate the contributions that the post-translational modifications of the G gamma subunit have on the assembly, membrane association, and function of the G-protein trimer reveal that these modifications are required for important protein-protein, in addition to membrane-protein, interactions.
Topics: Animals; GTP-Binding Proteins; Protein Prenylation; Signal Transduction
PubMed: 8958445
DOI: 10.1016/s0898-6568(96)00071-x -
Accounts of Chemical Research Feb 2015CONSPECTUS: The role dynamics plays in proteins is of intense contemporary interest. Fundamental insights into how dynamics affects reactivity and product distributions... (Review)
Review
CONSPECTUS: The role dynamics plays in proteins is of intense contemporary interest. Fundamental insights into how dynamics affects reactivity and product distributions will facilitate the design of novel catalysts that can produce high quality compounds that can be employed, for example, as fuels and life saving drugs. We have used molecular dynamics (MD) methods and combined quantum mechanical/molecular mechanical (QM/MM) methods to study a series of proteins either whose substrates are too far away from the catalytic center or whose experimentally resolved substrate binding modes cannot explain the observed product distribution. In particular, we describe studies of farnesyl transferase (FTase) where the farnesyl pyrophosphate (FPP) substrate is ∼8 Å from the zinc-bound peptide in the active site of FTase. Using MD and QM/MM studies, we explain how the FPP substrate spans the gulf between it and the active site, and we have elucidated the nature of the transition state (TS) and offered an alternate explanation of experimentally observed kinetic isotope effects (KIEs). Our second story focuses on the nature of substrate dynamics in the aromatic prenyltransferase (APTase) protein NphB and how substrate dynamics affects the observed product distribution. Through the examples chosen we show the power of MD and QM/MM methods to provide unique insights into how protein substrate dynamics affects catalytic efficiency. We also illustrate how complex these reactions are and highlight the challenges faced when attempting to design de novo catalysts. While the methods used in our previous studies provided useful insights, several clear challenges still remain. In particular, we have utilized a semiempirical QM model (self-consistent charge density functional tight binding, SCC-DFTB) in our QM/MM studies since the problems we were addressing required extensive sampling. For the problems illustrated, this approach performed admirably (we estimate for these systems an uncertainty of ∼2 kcal/mol), but it is still a semiempirical model, and studies of this type would benefit greatly from more accurate ab initio or DFT models. However, the challenge with these methods is to reach the level of sampling needed to study systems where large conformational changes happen in the many nanoseconds to microsecond time regimes. Hence, how to couple expensive and accurate QM methods with sophisticated sampling algorithms is an important future challenge especially when large-scale studies of catalyst design become of interest. The use of MD and QM/MM models to elucidate enzyme catalytic pathways and to design novel catalytic agents is in its infancy but shows tremendous promise. While this Account summarizes where we have been, we also discuss briefly future directions that improve our fundamental ability to understand enzyme catalysis.
Topics: Farnesyltranstransferase; Molecular Dynamics Simulation; Protein Prenylation; Quantum Theory
PubMed: 25539152
DOI: 10.1021/ar500321u -
Recent Progress in Hormone Research 1994
Review
Topics: Alkyl and Aryl Transferases; Animals; GTP-Binding Proteins; Macromolecular Substances; Protein Prenylation; Signal Transduction; Transferases
PubMed: 8146425
DOI: 10.1016/b978-0-12-571149-4.50015-5 -
Current Opinion in Chemical Biology Feb 1998A specific set of proteins in eukaryotic cells contain covalently attached carboxy-terminal prenyl groups (15-carbon farnesyl and 20-carbon geranylgeranyl). Many of them... (Review)
Review
A specific set of proteins in eukaryotic cells contain covalently attached carboxy-terminal prenyl groups (15-carbon farnesyl and 20-carbon geranylgeranyl). Many of them are signaling proteins including Ras, heterotrimeric G proteins and Rab proteins. The protein prenyltransferases which attach prenyl groups to proteins have been well characterized, and an X-ray structure is available for protein farnesyltransferase. Inhibitors of protein farnesyltransferase are showing sufficient promise in preclinical trials as anti-cancer drugs to warrant widespread interest in the pharmaceutical industry.
Topics: Alkyl and Aryl Transferases; Antineoplastic Agents; Humans; Protein Prenylation
PubMed: 9667914
DOI: 10.1016/s1367-5931(98)80034-3 -
International Journal of Molecular... Dec 2019The members of Rho family of GTPases, RhoA and Rac1 regulate endothelial cytoskeleton dynamics and hence barrier integrity. The spatial activities of these GTPases are...
The members of Rho family of GTPases, RhoA and Rac1 regulate endothelial cytoskeleton dynamics and hence barrier integrity. The spatial activities of these GTPases are regulated by post-translational prenylation. In the present study, we investigated the effect of prenylation inhibition on the endothelial cytoskeleton and barrier properties. The study was carried out in human umbilical vein endothelial cells (HUVEC) and protein prenylation is manipulated with various pharmacological inhibitors. Inhibition of either complete prenylation using statins or specifically geranylgeranylation but not farnesylation has a biphasic effect on HUVEC cytoskeleton and permeability. Short-term treatment inhibits the spatial activity of RhoA/Rho kinase (Rock) to actin cytoskeleton resulting in adherens junctions (AJ) stabilization and ameliorates thrombin-induced barrier disruption whereas long-term inhibition results in collapse of endothelial cytoskeleton leading to increased basal permeability. These effects are reversed by supplementing the cells with geranylgeranyl but not farnesyl pyrophosphate. Moreover, long-term inhibition of protein prenylation results in basal hyper activation of RhoA/Rock signaling that is antagonized by a specific Rock inhibitor or an activation of cAMP signaling. In conclusion, inhibition of geranylgeranylation in endothelial cells (ECs) exerts biphasic effect on endothelial barrier properties. Short-term inhibition stabilizes AJs and hence barrier function whereas long-term treatment results in disruption of barrier properties.
Topics: Cell Membrane Permeability; Cytoskeleton; Endothelial Cells; Endothelium; GTP Phosphohydrolases; Humans; Intercellular Junctions; Models, Biological; Protein Prenylation; rho-Associated Kinases
PubMed: 31861297
DOI: 10.3390/ijms21010002